Neisseria gonorrhoeae is the etiologic agent of the sexually transmitted infection, gonorrhea. Antibiotics are the mainstay in treating infections, but widespread resistance in N. gonorrhoeae, most notably emerging resistance to ceftriaxone, may soon result in strains that are untreatable with current antibiotics. Thus, new antibiotics against novel targets are desperately needed to stem the tide of resistant bacteria that are becoming a major threat to public health. The goal of this proposal is to optimize inhibitors of LpxC, an essential enzyme in the lipid A biosynthetic pathway, for treatment of N. gonorrhoeae infections. Preliminary data demonstrate that LpxC inhibitors are bactericidal for N. gonorrhoeae and are largely unaffected by established resistance mechanisms. Further development of these novel compounds will be achieved by (1) lead optimization of LpxC inhibitors, (2) evaluation of pharmacokinetic and pharmacodynamic properties of lead compounds, and (3) evaluation of antibiotic efficacies in a mouse model of infection. At the completion of this project, we anticipate having one or more LpxC inhibitors with good pharmacokinetic and pharmacodynamic properties that are potent and efficacious against N. gonorrhoeae both in vitro and in vivo. These studies would meet a number of benchmarks required for assembling an investigational new drug application to the FDA for approval of a new class of antibiotics for treatment of N. gonorrhoeae and other Gram-negative infections.